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Published on: May 28, 2014
Development of a cobalt(iii)-based ponatinib prodrug system
Marlene Mathuber1, Michael Gutmann2, Mery La Franca2,3
1Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna Waehringer Straße 42 1090 Vienna Austria.
Abstract:
Receptor tyrosine kinase inhibitors have become a central part of modern targeted cancer therapy. However, their curative potential is distinctly limited by both rapid resistance development and severe adverse effects. Consequently, tumor-specific drug activation based on prodrug designs, exploiting tumor-specific properties such as hypoxic oxygen conditions, is a feasible strategy to widen the therapeutic window. After proof-of-principal molecular docking studies, we have synthesized two cobalt(iii) complexes using a derivative of the clinically approved Abelson (ABL) kinase and fibroblast growth factor receptor (FGFR) inhibitor ponatinib. Acetylacetone (acac) or methylacetylacetone (Meacac) have been used as ancillary ligands to modulate the reduction potential. The ponatinib derivative, characterized by an ethylenediamine moiety instead of the piperazine ring, exhibited comparable cell-free target kinase inhibition potency. Hypoxia-dependent release of the ligand from the cobalt(iii) complexes was proven by changed fluorescence properties, enhanced downstream signaling inhibition and increased in vitro anticancer activity in BCR-ABL- and FGFR-driven cancer models. Respective tumor-inhibiting in vivo effects in the BCR-ABL-driven K-562 leukemia model were restricted to the cobalt(iii) complex with the higher reduction potential and confirmed in a FGFR-driven urothelial carcinoma xenograft model. Summarizing, we here present for the first time hypoxia-activatable prodrugs of the clinically approved tyrosine kinase inhibitor ponatinib and a correlation of the in vivo activity with their reduction potential.
Insights
Researchers developed hypoxia-activated prodrugs of the tyrosine kinase inhibitor ponatinib. These novel cobalt(iii) complexes show tumor-specific drug release and enhanced anticancer activity in preclinical models.
Area of Science:
- Medicinal Chemistry
- Oncology
- Coordination Chemistry
Background:
- Receptor tyrosine kinase inhibitors (RTKIs) are crucial in targeted cancer therapy but face challenges with resistance and toxicity.
- Tumor-specific drug activation via prodrug strategies, leveraging conditions like hypoxia, can improve therapeutic windows.
- Ponatinib is a clinically approved RTKI targeting BCR-ABL and FGFR, but its use is limited by side effects.
Purpose of the Study:
- To design and synthesize novel hypoxia-activatable prodrugs of ponatinib.
- To investigate the tumor-specific release mechanism and in vitro/in vivo efficacy of these prodrugs.
- To establish a correlation between the reduction potential of cobalt(iii) complexes and their in vivo anticancer activity.
Main Methods:
- Molecular docking studies were performed to guide prodrug design.
- Two cobalt(iii) complexes incorporating a ponatinib derivative with acetylacetone or methylacetylacetone ligands were synthesized.
- In vitro assays assessed kinase inhibition, hypoxia-dependent ligand release (via fluorescence, signaling inhibition), and anticancer activity.
- In vivo studies evaluated tumor inhibition in BCR-ABL-driven leukemia and FGFR-driven urothelial carcinoma models.
Main Results:
- The synthesized ponatinib derivative retained potent cell-free kinase inhibition.
- Hypoxia-dependent release of the active ponatinib ligand from cobalt(iii) complexes was confirmed.
- Significant in vitro anticancer activity was observed in BCR-ABL- and FGFR-driven cancer models under hypoxic conditions.
- In vivo tumor inhibition was observed, with efficacy correlating to the cobalt(iii) complex's reduction potential in both leukemia and urothelial carcinoma models.
Conclusions:
- The study presents the first hypoxia-activatable prodrugs of the tyrosine kinase inhibitor ponatinib.
- These prodrugs demonstrate tumor-specific activation and enhanced efficacy in preclinical cancer models.
- The reduction potential of the cobalt(iii) complexes is a critical factor influencing their in vivo therapeutic activity.
